Process for producing lactone

ABSTRACT

A method for producing lactones, which comprises reacting an amide compound of Formula (I): 
                         
[wherein X represents a halogen atom; R, R′ and R 1  to R 6  each independently represents a hydrogen atom or any desired substituent; and n represents an integer of 0 to 2] with an aqueous medium.

TECHNICAL FIELD

The present invention relates to a method for producing lactones.Lactones are useful as starting materials or solvents for synthesis ofvarious compounds, such as pharmaceutical preparations and agriculturalchemicals, etc.

BACKGROUND ART

A lactone is a cyclic compound containing an ester group in the ring,and those having 3, 4, 5, 6 and 7 ring members are referred to as α-,β-, γ-, δ- and ε-lactones, respectively. Many strategies are known forsynthesis of lactones, including those using an acid catalyst tosynthesize γ-butyrolactones from 4-hydroxybutyric acids, as well asthose involving, e.g., reduction of succinic anhydrides or heating of4-halogenated butyric acids to synthesize γ-butyrolactones.

However, although depending on the types of γ-butyrolactones to beproduced, most of these strategies are associated with problems such asformation of byproducts, low yield, risks of explosion, and difficultsynthesis of starting materials. Thus, there has been a strong need todevelop a novel synthesis method.

To produce 3-hydroxy-γ-butyrolactones by organic synthesis, for example,glycidol and carbon monoxide may be reacted at elevated temperature andpressure in the presence of a noble metal catalyst (U.S. Pat. No.4,968,817), or 3-butenoic acid may be epoxidized by treatment withhydrogen peroxide in the presence of a platinum catalyst and thenhydrated and converted into a lactone (Angew. chem., Int. Ed. Eng994-1000 (1966)). However, these methods are associated with increasedrisks of explosion, etc. Also known are a 7-step process starting withL-ascorbic acid or D-isoascorbic acid (Synthesis 570-572 (1987)) and a3-step process starting with L-malic acid (JP-A-6-172256). However,these processes require complicated procedures and also fail to producesuccessful results in terms of yield because they involve multi-stepreactions.

In addition, 3-hydroxy-γ-butyrolactones are known to be produced bybiological processes using Pseudomonas or Enterobacter bacteria as amicrobial catalyst to produce (S)-3-hydroxy-γ-butyrolactone from ethyl4-chloro-3-hydroxybutyrate [see, e.g., Tetrahedr. Asym. 11. 3109-3112(1996)]. However, such biological processes are not successful in termsof enzyme stability. Also, they cannot be regarded as industriallyadvantageous because complicated procedures are required to preparesubstrates.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide an industriallyadvantageous method for producing lactones, particularlyγ-butyrolactones or δ-valerolactones, starting with easily synthesizableamides. This method can be carried out under mild conditions and reducesteps and the risk of byproduct formation.

As a result of extensive and intensive efforts made to overcome theproblems stated above, the inventors of the present invention havesurprisingly found that the reaction between 4-halo-butylamides andwater causes rapid elimination of halogen and ammonia to givecorresponding γ-butyrolactones in high yield. This finding led to thecompletion of the present invention.

Namely, the present invention is directed to a method for producinglactones, which comprises reacting an amide compound of Formula (I):

[wherein X represents a halogen atom; R, R′ and R₁ to R₆ eachindependently represents a hydrogen atom or any desired substituent; andn represents an integer of 0 to 2] with an aqueous medium.

Also, the present invention is directed to a method for producingγ-butyrolactones, which comprises reacting a 4-halo-butylamide ofFormula (II):

[wherein X represents a halogen atom, and R₁ to R₆ each independentlyrepresents a hydrogen atom or any desired substituent] with an aqueousmedium to give a γ-butyrolactone of Formula (III):

[wherein R₁ to R₆ each independently represents a hydrogen atom or anydesired substituent].

In the above method, the 4-halo-butylamide of Formula (II) may be, forexample, a 4-halo-3-hydroxybutylamide. Examples of the compoundrepresented by Formula (II) include those obtained by nitrile hydratasetreatment of a 4-halo-butyronitrile having Formula (IV):

[wherein X represents a halogen atom, and R₁ to R₆ each independentlyrepresents a hydrogen atom or any desired substituent]. The phrase“nitrile hydratase treatment” is intended to mean hydration by thecatalytic action of nitrile hydratase.

Examples of nitrile hydratase as used herein include those produced byat least one microorganism belonging to any genus selected from thegroup consisting of Arthrobacter, Brevibacterium, Caseobacter,Corynebacterium, Pseudomonas and Rhodococcus or those produced by mixedmicroorganisms composed of at least one microorganism belonging to onegenus selected from the group listed above and at least onemicroorganism belonging to another genus selected from the group listedabove. Alternatively, nitrile hydratase may be produced by transformantscarrying a gene encoding nitrile hydratase.

Further, the present invention is directed to a method for producingδ-valerolactones, which comprises reacting a 5-halo-pentylamide ofFormula (V):

[wherein X represents a halogen atom, and R₁ to R₈ each independentlyrepresents a hydrogen atom or any desired substituent] with an aqueousmedium to give a δ-valerolactone of Formula (VI):

[wherein R₁ to R₈ each independently represents a hydrogen atom or anydesired substituent].

In the above method, the reaction may be carried out, for example, at atemperature of 30° C. to 100° C. and at a pH of 1.0 to 6.0.

The present invention will be described in more detail below.

The present invention aims to effect a reaction between an amidecompound of the above Formula (I) and an aqueous medium to causeelimination of halogen and ammonia, thereby obtaining lactones ofinterest. The present invention enables the provision of a fewer-stepand higher-yield method for producing lactones. In particular, it isbeyond all expectations that γ-butyrolactones could be produced from4-halo-butylamides.

In Formula (I), n represents an integer of 0 to 2 and X represents ahalogen atom. A halogen atom is intended to mean a fluorine atom, achlorine atom, a bromine atom or an iodine atom, with a chlorine atombeing preferred. When n is 0, the amide compound to be used as astarting material is a 4-halo-butylamide of Formula (II):

and the resulting lactone is a γ-butyrolactone of Formula (III):

When n is 1, the amide compound to be used as a starting material is a5-halo-pentylamide of Formula (V):

and the resulting lactone is a δ-valerolactone of Formula (VI):

Likewise, when n is 2, the amide compound to be used as a startingmaterial is a 6-halo-hexylamide and the resulting lactone is anε-caprolactone.

In Formulae (I) to (VI), R₁ to R₈ as well as R and R′ (when n=1 inFormula (I), R and R′ correspond to R₇ and R₈, respectively) may be thesame or different and each independently represents a hydrogen atom orany desired substituent. The term “any desired substituent” as usedherein is intended to mean an optionally substituted C₁-C₂₀ hydrocarbongroup (i.e., containing 1 to 20 carbon atoms), an optionally substitutedC₁-C₂₀ alkoxy group (i.e., containing 1 to 20 carbon atoms), anoptionally substituted C₆-C₂₀ aryloxy group (i.e., containing 6 to 20carbon atoms), an optionally substituted C₇-C₂₀ alkylaryloxy group(i.e., containing 7 to 20 carbon atoms), an optionally substitutedC₂-C₂₀ alkoxycarbonyl group (i.e., containing 2 to 20 carbon atoms), anoptionally substituted amino group, an optionally substituted silylgroup or a hydroxyl group. Alternatively, it may be an optionallysubstituted alkylthio group, an optionally substituted arylthio group,an optionally substituted alkylsulfonyl group or an optionallysubstituted arylsulfonyl group.

Such a hydrocarbon group may be either a saturated or unsaturatedacyclic (open chain) group or a saturated or unsaturated cyclic group.In a case where the hydrocarbon group is acyclic, it may be eitherlinear or branched. Examples of such a hydrocarbon group include aC₁-C₂₀ alkyl group, a C₂-C₂₀ alkenyl group, a C₂-C₂₀ alkynyl group, aC₄-C₂₀ alkyldienyl group, a C₆-C₁₈ aryl group, a C₆-C₂₀ alkylaryl group,a C₆-C₂₀ arylalkyl group, a C₄-C₂₀ cycloalkyl group, a C₄-C₂₀cycloalkenyl group and a (C₃-C₁₀ cycloalkyl)-C₁-C₁₀ alkyl group.

The C₁-C₂₀ alkyl group is preferably a C₁-C₁₀ alkyl group. Examples ofsuch an alkyl group include, for example, a methyl group, an ethylgroup, a propyl group, an isopropyl group, an n-butyl group, a sec-butylgroup, a tert-butyl group, a pentyl group, a hexyl group, an octylgroup, a nonyl group, a decyl group, a undecyl group and a dodecylgroup.

The C₂-C₂₀ alkenyl group is preferably a C₂-C₁₀ alkenyl group. Examplesof such an alkenyl group include, for example, a vinyl group, an allylgroup, a propenyl group, an isopropenyl group, a 2-methyl-1-propenylgroup, a 2-methylallyl group and a 2-butenyl group.

The C₂-C₂₀ alkynyl group is preferably a C₂-C₁₀ alkynyl group. Examplesof such an alkynyl group include, for example, an ethynyl group, apropynyl group and a butynyl group.

The C₄-C₂₀ alkyldienyl group is preferably a C₄-C₁₀ alkyldienyl group.Examples of such an alkyldienyl group include, for example, a1,3-butadienyl group.

The C₆-C₁₈ aryl group is preferably a C₆-C₁₀ aryl group. Examples ofsuch an aryl group include, for example, a phenyl group, a 1-naphthylgroup, a 2-naphthyl group, an indenyl group, a biphenyl group, ananthryl group and a phenanthryl group.

The C₆-C₂₀ alkylaryl group is preferably a C₆-C₁₂ alkylaryl group.Examples of such an alkylaryl group include, for example, a o-tolylgroup, a m-tolyl group, a p-tolyl group, a 2,3-xylyl group, a 2,4-xylylgroup, a 2,5-xylyl group, a o-cumenyl group, a m-cumenyl group, ap-cumenyl group and a mesityl group.

The C₆-C₂₀ arylalkyl group is preferably a C₆-C₁₂ arylalkyl group.Examples of such an arylalkyl group include, for example, a benzylgroup, a phenethyl group, a 1-naphthylmethyl group, a 2-naphthylmethylgroup, a 1-phenylethyl group, a phenylpropyl group, a phenylbutyl group,a phenylpentyl group, a phenylhexyl group, a methylbenzyl group, adimethylbenzyl group, a trimethylbenzyl group, an ethylbenzyl group, amethylphenethyl group, a dimethylphenethyl group and a diethylbenzylgroup.

The C₄-C₂₀ cycloalkyl group is preferably a C₄-C₁₀ cycloalkyl group.Examples of such a cycloalkyl group include, for example, a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, acycloheptyl group and a cyclooctyl group.

The C₄-C₂₀ cycloalkenyl group is preferably a C₄-C₁₀ cycloalkenyl group.Examples of such a cycloalkenyl group include, for example, acyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, acyclopentadienyl group and a cyclohexenyl group.

The C₁-C₂₀ alkoxy group is preferably a C₁-C₁₀ alkoxy group. Examples ofsuch an alkoxy group include, for example, a methoxy group, an ethoxygroup, a propoxy group, a butoxy group and a pentyloxy group.

The C₆-C₂₀ aryloxy group is preferably a C₆-C₁₀ aryloxy group. Examplesof such an aryloxy group include, for example, a phenyloxy group, anaphthyloxy group and a biphenyloxy group.

The C₇-C₂₀ alkylaryloxy group is preferably a C₇-C₁₂ alkylaryloxy group.Examples of such an alkylaryloxy group include, for example, amethylphenyloxy group, an ethylphenyloxy group, a propylphenyloxy group,a butylphenyloxy group, a dimethylphenyloxy group, a diethylphenyloxygroup, a dipropylphenyloxy group, a dibutylphenyloxy group, amethylethylphenyloxy group, a methylpropylphenyloxy group and anethylpropylphenyloxy group.

The C₂-C₂₀ alkoxycarbonyl group is preferably a C₂-C₁₀ alkoxycarbonylgroup. Examples of such an alkoxycarbonyl group include, for example, amethoxycarbonyl group, an ethoxycarbonyl group, a2-methoxyethoxycarbonyl group and a t-butoxycarbonyl group.

The optionally substituted amino group listed above encompasses, forexample, an amino group, a dimethylamino group, a methylamino group, amethylphenylamino group and a phenylamino group.

The optionally substituted silyl group listed above encompasses, forexample, a dimethylsilyl group, a diethylsilyl group, a trimethylsilylgroup, a triethylsilyl group, a trimethoxysilyl group, a triethoxysilylgroup, a diphenylmethylsilyl group, a triphenylsilyl group, atriphenoxysilyl group, a dimethylmethoxysilyl group, adimethylphenoxysilyl group and a methylmethoxyphenyl group.

The present invention is characterized by using, as a solvent, anaqueous medium that is extremely inexpensive and safe for handling whencompared to other organic solvents. Examples of such an aqueous mediuminclude tap water and distilled water, as well as phosphate buffer,Tris-HCl buffer, acetate buffer, borate buffer, etc.

For use in the reaction of the present invention, amides (e.g.,4-halo-butylamides) and an aqueous medium may be mixed at any ratio.There is no particular limitation on the amount of an aqueous medium tobe used, but in general, it is preferably in the range of 1- to1000-fold excess (by weight), more preferably 2- to 100-fold excess (byweight), relative to Compound (I). To prepare a reaction mixture ofthese materials, the aqueous medium and amides may be mixed all at once,or alternatively, the amides may be added in divided portions and mixedinto a given volume of the aqueous medium.

Also, the reaction mixture may contain an appropriate buffer, e.g., forthe purpose of facilitating pH adjustment and/or may contain anappropriate organic solvent, e.g., for the purpose of increasing thesolubility of 4-halo-butylamides.

The reaction temperature can be selected as appropriate for thestability of starting materials, etc. For example, it ranges from 30° C.to 100° C., preferably 50° C. to 70° C., and more preferably is 70° C.

The pH at which the reaction is conducted ranges, for example, from 1.0to 6.0, preferably 1.2 to 5, and more preferably is 3.5. If pH isdecreased during the reaction, it is effective to adjust pH with anappropriate alkali (e.g., NaOH, KOH, ammonia, etc.). By way of example,in the reaction where 3-hydroxy-γ-butyrolactone is produced from a4-halo-3-hydroxybutylamide, 3-hydroxy-γ-butyrolactone can be obtained inhigher yield when the reaction mixture is adjusted with an alkali to pH1.2 to pH 5 than in the case of using no pH adjustment.

Lactones produced and accumulated in the reaction mixture may becollected and purified in a known manner. For example, in the case ofproducing γ-butyrolactones, if γ-butyrolactones of interest are notwater-soluble, they can be obtained by phase separation. In contrast, ifγ-butyrolactones of interest are water-soluble, they can be obtained bydistillation of water or extraction with an appropriate solvent.

Examples of such an extraction solvent include pyrrolidones, methylethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate,n-butanol, isobutanol, hexane and toluene, which may be selected asappropriate for each case. Since ammonium halides are also generated inthe reaction mixture, appropriate salts may be added as needed toseparate ammonium halides as a separate phase. This allows phaseseparation even in the case of using a water-soluble solvent such asacetonitrile or tert-butanol, and is particularly effective in theproduction of highly hydrophilic γ-butyrolactones. Also, distillation orother treatments can be used for further purification.

In the present invention, amides (e.g., 4-halo-butylamides) may beobtained using standard procedures for amide synthesis, for example, byammonia treatment of an acid chloride or an acid anhydride or an esterthereof, dehydration condensation between carboxylic acid and ammonia atan elevated temperature, or hydration of corresponding4-halo-butyronitriles with a mineral acid or an alkali.

However, hydration of nitriles catalyzed by nitrile hydratase is morepreferred because it is excellent in yield and purity.

An explanation will be given of a case where 4-halo-butyronitriles arehydrated.

In this case, nitrile hydratases of any origin may be used as long asthey are capable of converting 4-halo-butyronitriles of the followingFormula (IV):

into 4-halo-butylamides of the following Formula (II):

Examples of microorganisms containing these nitrile hydratases include,for example, those belonging to Arthrobacter, Brevibacterium,Caseobacter, Corynebacterium, Pseudomonas or Rhodococcus. Specificexamples include Arthrobacter oxydans IFO 12138, Brevibacterium helvolumATCC 11822, Corynebacterium flavescens IAM 1642, Rhodococcuserythropolis IFO 12540 and Rhodococcus erythropolis IFO 12539, all ofwhich are readily available from the American Type Culture Collection(ATCC), the Institute for Fermentation, Osaka (IFO) or the Institute ofApplied Microbiology (IAM), the University of Tokyo.

Further examples include Arthrobacter sp. SK103, Caseobacter sp. BC23,Rhodococcus rhodochrous J-1 [FERM BP-1478: International Patent OrganismDepositary, National Institute of Advanced Industrial Science andTechnology (Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan),received on Sep. 18, 1987]. Pseudomonas sp. BC15-2 [FERM BP-3320:International Patent Organism Depositary, National Institute of AdvancedIndustrial Science and Technology (Central 6, 1-1-1 Higashi, Tsukuba,Ibaraki 305-8566, Japan), received on Mar. 18, 1991], Pseudomonas sp.SK31, Pseudomonas sp. SK87, Pseudomonas sp. SK13 [FERM BP-3325:International Patent Organism Depositary, National Institute of AdvancedIndustrial Science and Technology (Central 6, 1-1-1 Higashi, Tsukuba,Ibaraki 305-8566, Japan), received on Mar. 18, 1991], Rhodococcus sp.SK70, Rhodococcus sp. HR11 and Rhodococcus sp. SK49. Thesemicroorganisms can be found in Japanese Patent No. 3014171 and thoseskilled in the art can readily obtain them by reference to this patentdocument. Moreover, among these microorganisms, Rhodococcus rhodochrousJ-1 (FERM BP-1478), Pseudomonas sp. BC15-2 (FERM BP-3320) andPseudomonas sp. SK13 (FERM BP-3325) have been internationally depositedunder the Budapest Treaty. A list of deposit information is as indicatedbelow.

Microorganism Labeled as: Deposit date Accession No. RhodococcusRhodococcus 1987/09/18 FERM BP-1478 rhodochrous rhodochrous J-1 J-1Pseudomonas Pseudomonas 1991/03/18 FERM BP-3320 sp. BC15-2 sp. BC15-2Pseudomonas Pseudomonas 1991/03/18 FERM BP-3325 sp. SK13 sp. SK13

In the present invention, microorganisms belonging to any genus listedabove can be used either alone or in combination. Alternatively, it isalso possible to use mixed microorganisms composed of one or moremicroorganisms belonging to one genus listed above and one or moremicroorganisms belonging to another genus listed above.

Moreover, it is possible to use microorganisms transformed with a geneencoding nitrile hydratase which may be taken from the above-listedmicroorganisms and expressed using an appropriate host-vector system.

By way of example, chromosomal DNA is prepared from the above-listedmicroorganisms to construct a chromosomal DNA library using anappropriate plasmid vector. Cloning of the nitrile hydratase gene can beaccomplished, for example, by colony hybridization or other techniques.PCR primers are designed from a partial amino acid sequence (e.g.,N-terminal sequence) of nitrile hydratase and used for PCR with thechromosomal DNA library as a template to obtain a DNA fragment ofinterest. The nucleotide sequence of DNA encoding nitrile hydratase isdetermined using a commercially available nucleotide sequencer.

To produce nitrile hydratase using the resulting nitrile hydratase gene,the gene is first linked to an appropriate expression vector toconstruct a plasmid, which is then introduced into, e.g., an appropriatehost to obtain a transformant.

Cloning and gene recombination techniques for the nitrile hydratase geneare well known in the art (see, e.g., Japanese Patent No. 2840253 and2907479).

Subsequently, upon culturing this transformant, a huge amount of nitrilehydratase is produced in the host cells. Although this enzyme may beused for the conversion reaction in the form of bacterial cells, it isused either as a cell-free extract or in a purified form after crushingthe bacterial cells.

In general, any culture medium can be used for culturing theabove-listed microorganisms as long as it allows the growth of thesemicroorganisms. Examples of a carbon source available for use includesaccharides such as glucose, fructose, sucrose and maltose, organicacids such as acetic acid and citric acid, as well as alcohols such asethanol and glycerol. Examples of a nitrogen source available for useinclude naturally-occurring normal nitrogen sources such as peptone,meat extracts, yeast extracts, protein hydrolysates and amino acids, aswell as ammonium salts of various inorganic and organic acids. Ifnecessary, the culture medium may further be supplemented, asappropriate, with inorganic salts, trace minerals, vitamins, etc.

To induce higher nitrile hydratase activity, it may also be effective tosupplement the culture medium with various nitrile compounds such asn-propionitrile, n-butyronitrile, isobutyronitrile,4-chloro-3-hydroxybutyronitrile and benzyl cyanide, various amidecompounds such as n-propionamide, n-butylamide and isobutylamide, and/orlactam compounds such as γ-butyrolactam, δ-valerolactam andε-caprolactam, etc.

The above-listed microorganisms may be cultured in accordance withstandard procedures, for example, under aerobic conditions for 10 to 180hours in the range of pH 4 to pH 10 and temperature 10° C. to 40° C.Both liquid and solid culture systems may be used for this purpose.

In the above reaction, nitrile hydratase may be used in a crude orpurified form, or alternatively, in the form of a cultured solution ofmicroorganisms, bacterial cells isolated by filtration orcentrifugation, crushed bacterial cells, a bacterial cell extract, etc.The enzyme of these forms may further be immobilized on an appropriatecarrier (e.g., acrylamide, carragheenan, agarose) or adsorbed on an ionexchange resin or the like. The form to be used is selected asappropriate for the mode of reaction. Possible modes of reaction includethose in which the reaction is conducted simultaneously with culturingof microorganisms in the presence of reaction substrates, those in whichnitrile hydratase of these forms is suspended in an appropriate aqueousmedium, if necessary, and added to reaction substrates, and those inwhich reaction substrates are added to nitrile hydratase of these formssuspended in an aqueous medium.

Examples of an aqueous medium used for the nitrile hydratase reactioninclude water as well as other water-based media supplemented with,e.g., buffers containing salts of organic acids, phosphoric acid, boricacid or amines, other salts and/or organic solvents, as needed. There isno particular limitation on the temperature and pH used for thereaction, but they are desirably set within the ranges of 0° C. to 50°C. and pH 3 to pH 10, respectively.

4-Halo-butylamides may be converted into γ-butyrolactones simultaneouslywith and/or subsequent to the production of 4-halo-butylamides from4-halo-butyronitriles by the action of nitrile hydratase.

In this case, in order to obtain γ-butyrolactones in high yield, thenitrile hydratase-catalyzed reaction is preferably conducted at 0° C. to50° C. and, after consuming 4-halo-butyronitriles as much as possible,the temperature is preferably set at 30° C. to 100° C. for theconversion reaction into γ-butyrolactones.

Since the production of 4-halo-butylamides from 4-halo-butyronitrilesand the production of γ-butyrolactones from 4-halo-butylamides are bothusually exothermic reactions, the reaction vessel should be cooled bymeans of jackets, internal coils, heat exchangers or the like, ifnecessary.

Moreover, these reactions, collection, purification and other processes,if any, can be accomplished in either a batch or continuous fashion.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be further described in more detail in thefollowing Examples, which are not intended to limit the scope of theinvention.

EXAMPLE 1

An aqueous solution of 4-chloro-3-hydroxybutylamide (34.5% by mass, 100ml) was reacted in a water bath at 70° C. for 3 hours.

To confirm β-hydroxy-γ-butyrolactone present in the reaction mixture,the reaction mixture was extracted with ethyl acetate and evaporatedunder reduced pressure to remove the solvent, followed by analysis ofthe residue by IR, ¹H-NMR and ¹³C-NMR. Each compound was quantifiedusing high performance liquid chromatography under the followingconditions.

<Analysis Conditions for High Performance Liquid Chromatography>

Column: Inertsil ODS-3V (4.6 mm ID×25 mm), a product of GL Sciences,Inc.

Mobile phase: 0.1% phosphoric acid in water

Flow rate: 1 ml/min

Column temperature: 40° C.

Detection: differential refractometer (Japan Spectroscopic Co., Ltd.)

As a result, the amount of residual 4-chloro-3-hydroxybutylamide was 1%or less of the initial amount and the yield of β-hydroxy-γ-butyrolactonewas 65.2%. The final pH at the completion of the reaction was 0.9. Inaddition, 4-chloro-3-hydroxybutyric acid was not detected either duringor after the reaction.

EXAMPLE 2

An aqueous solution of 4-chloro-3-hydroxybutylamide (34.5% by mass, 100ml, containing 20 mM phosphate buffer) was reacted in a water bath at70° C. for 3 hours. During the reaction, a pH controller was used tomaintain a pH of 1.2, 2.0, 3.0, 3.5, 4.0, 4.5, 5.0 or 5.5 by adjustingwith 24% by mass NaOH. The results were compared to the case where pHwas not controlled.

β-Hydroxy-γ-butyrolactone present in the reaction mixture was quantifiedin the same manner as used in Example 1, indicating that the amount ofresidual 4-chloro-3-hydroxybutylamide was 1% or less of the initialamount in each case. The yield of β-hydroxy-γ-butyrolactone was as shownin Table 1 below. In the case where pH was not controlled, the final pHat the completion of the reaction was 1.0.

In addition, 4-chloro-3-hydroxybutyric acid was not detected eitherduring or after the reaction in each case.

TABLE 1 pH Uncon- trolled 1.2 2 3 3.5 4 4.5 5 5.5 Yield 65.8 69.8 73.279.6 85.2 78.4 73.4 66.4 56.5 [%]

EXAMPLE 3

An aqueous solution of 4-chloro-3-hydroxybutylamide (34.5% by mass, 100ml, containing 20 mM phosphate buffer) was reacted in a water bath at30° C., 50° C., 70° C. or 100° C. until the amount of residual4-chloro-3-hydroxybutylamide was reduced to 1% by mole or less of theinitial amount. During the reaction, a pH controller was used tomaintain a pH of 3.5 by adjusting with 24% by mass NaOH.

β-Hydroxy-γ-butyrolactone present in the reaction mixture was quantifiedin the same manner as used in Example 1. The yields obtained were asshown in Table 2 below. In addition, 4-chloro-3-hydroxybutyric acid wasnot detected either during or after the reaction in each case.

TABLE 2 Reaction temperature [° C.] 30 50 70 100 Yield [%] 94.6 88.685.4 84.8 Reaction time [hr] 336 15 3 0.5

EXAMPLE 4

An aqueous solution of 4-chloro-3-hydroxybutylamide at a concentrationof 11.5%, 23% or 34.5% by mass (100 ml, containing 20 mM phosphatebuffer) was reacted in a water bath at 70° C. until the amount ofresidual 4-chloro-3-hydroxybutylamide was reduced to 1% by mole or lessof the initial amount. During the reaction, a pH controller was used tomaintain a pH of 3.5 by adjusting with 24% NaOH.

β-Hydroxy-γ-butyrolactone present in the reaction mixture was quantifiedin the same manner as used in Example 1. The yields obtained were asshown in Table 3 below. In addition, 4-chloro-3-hydroxybutyric acid wasnot detected either during or after the reaction in each case.

TABLE 3 Initial concentration [%] 11.5 23 34.5 Yield [%] 94.8 91.3 85.2Reaction time [hr] 2 2.5 3

EXAMPLE 5

An aqueous solution of 4-chloro-3-hydroxybutylamide (23% by mass, 100ml, containing 20 mM phosphate buffer) was reacted in a water bath at70° C. until the amount of residual 4-chloro-3-hydroxybutylamide wasreduced to 1% by mole or less of the initial amount. During thereaction, a pH controller was used to maintain a pH of 3.5 by adjustingwith 24% NaOH.

After the reaction, methyl ethyl ketone (50 mL) was added to 50 mL ofthe reaction mixture, followed by vigorous stirring and phase separationto collect the organic layer. This procedure was repeated three timesand the resulting organic layer (about 170 mL) was evaporated on arotary evaporator at a water bath temperature of 60° C. and at 10 torrto remove volatile components, thereby obtaining a clear solution.

β-Hydroxy-γ-butyrolactone was quantified in the same manner as used inExample 1, indicating that the concentration ofβ-hydroxy-γ-butyrolactone was 94.5% and the water content was 0.2% asmeasured by the Karl Fischer method.

Upon addition of methyl ethyl ketone (200 mL), this solution becameclouded due to precipitates mainly composed of ammonium chloride. Theclouded solution was hence filtered under pressure through a 1 μm filterpaper and evaporated to remove volatile components in the same manner asdescribed above, thereby obtaining a clear solution. The concentrationof β-hydroxy-γ-butyrolactone was 98.1% and the water content was 0.1% orless. The total yield of β-hydroxy-γ-butyrolactone was 64.0%, ascalculated from the amount of 4-chloro-3-hydroxybutylamide initiallycharged.

EXAMPLE 6

An aqueous solution of 4-chloro-3-hydroxybutylamide (23% by mass, 100ml, containing 20 mM phosphate buffer) was reacted in a water bath at70° C. until the amount of residual 4-chloro-3-hydroxybutylamide wasreduced to 1% by mole or less of the initial amount. During thereaction, a pH controller was used to maintain a pH of 3.5 by adjustingwith 24% NaOH.

After the reaction, cyclohexanone (50 mL) was added to 50 mL of thereaction mixture and evaporated on a rotary evaporator at a water bathtemperature of 60° C. and at 60 torr to remove water and volatilecomponents. The residue became clouded due to precipitates mainlycomposed of ammonium chloride, and hence it was filtered under pressurethrough a 1 μm filter paper and then evaporated on a rotary evaporatorat a water bath temperature of 60° C. and at 10 torr to remove residualvolatile components.

β-Hydroxy-γ-butyrolactone was quantified in the same manner as used inExample 1, indicating that the concentration ofβ-hydroxy-γ-butyrolactone was 92.3% and the water content was 0.1% orless. The total yield of β-hydroxy-γ-butyrolactone was 90.4%, ascalculated from the amount of 4-chloro-3-hydroxybutylamide initiallycharged.

EXAMPLE 7

A medium (10 ml, pH 7.2) comprising glucose (10 g/l), K₂HPO₄ (0.5 g/l),KH₂PO₄ (0.5 g/l), MgSO₄.7H₂O (0.5 g/l), yeast extract (1 g/l) andpolypeptone (7.5 g/l) was introduced into a test tube, autoclaved at121° C. for 15 minutes, and then inoculated with Rhodococcus rhodochrousstrain J-1, followed by shaking culture at 28° C. for 48 hours. Theresulting culture was used as a preliminary culture.

The medium of the above ingredients was further supplemented with urea(15 g/l) and CoCl₂ (10 mg/l). The medium thus prepared (100 ml, pH 7.2)was introduced into a 500 ml Erlenmeyer flask, autoclaved at 121° C. for15 minutes., and then inoculated with the preliminary culture (4 ml),followed by shaking culture at 28° C. for 96 hours.

The bacterial cells thus cultured were collected by centrifugation andsuspended in an equal volume of 50 mM phosphate buffer (pH 7.7),followed by centrifugation to collect the cells. The cells weresuspended again in the same buffer (10 ml).

An aqueous solution (100 g) containing the bacterial cell suspensionthus prepared (10 g), 4-chloro-3-hydroxybutyronitrile (30 g) and 20 mMphosphate buffer (pH 7.0) was prepared and reacted at 30° C. for 1 hour.During the reaction, the temperature of the solution was elevated andhence the solution was cooled with water, as needed, to maintain atemperature of 30° C.

The yield of 4-chloro-3-hydroxybutylamide in the reaction mixture was99%, as quantified in the same manner as used in Example 1.

This solution was reacted in a water bath at 70° C. for 3 hours. Duringthe reaction, a pH controller was used to maintain a pH of 3.5 byadjusting with 24% by mass NaOH.

β-Hydroxy-γ-butyrolactone present in the reaction mixture was quantifiedin the same manner as used in Example 1, indicating that the yieldcalculated from 4-chloro-3-hydroxybutyronitrile was 84.3%.4-Chloro-3-hydroxybutyronitrile, 4-chloro-3-hydroxybutylamide and4-chloro-3-hydroxybutyric acid were not detected.

EXAMPLE 8

A methyl ethyl ketone solution (100 ml) containing 11.5% by mass of4-chloro-3-hydroxybutylamide and 10% by mass of water was reacted in awater bath at 60° C. for 24 hours.

The yield of β-hydroxy-γ-butyrolactone in the reaction mixture was 92%,as quantified in the same manner as used in Example 1. Likewise, thepercentage of residual 4-chloro-3-hydroxybutylamide was 5%, and4-chloro-3-hydroxybutyric acid was not detected either during or afterthe reaction.

REFERENCE EXAMPLE 1

Under the conditions disclosed in Japanese Patent No. 3014171,Rhodococcus rhodochrous J-1 was provided for the production of4-chloro-3-hydroxybutylamide from 4-chloro-3-hydroxybutyronitrile toconfirm whether β-hydroxy-γ-butyrolactone was produced.

A medium of the following composition was dispensed in aliquots of 5 mlinto test tubes and sterilized at 120° C. for 15 minutes. Aqueoussolutions (5% w/v) of isobutyronitrile and isobutylamide were eachsterilized through a membrane filter and added in a volume of 0.1 ml.Rhodococcus rhodochrous strain J-1 was inoculated into this medium andcultured with shaking at 30° C. for 72 hours. The bacterial cells werecollected by centrifugation and washed with 50 mM phosphate buffer (1.5ml, pH 7.2), followed by addition of 1 ml of 50 mM phosphate buffer (pH7.2) containing 88 mM 4-chloro-3-hydroxybutyronitrile. The reaction wascontinued at 20° C. for 24 hours.

Medium composition Glucose  0.5% KH₂PO₄  0.05% K₂HPO₄  0.05% MgSO₄•7H₂O 0.05% Yeast extract  0.2% Polypeptone  0.5% MgCl₂  0.04% KCl 0.004%MnSO₄ 0.4 × 10⁻³% FeCl₃ 0.6 × 10⁻⁵% ZnSO₄ 0.3 × 10⁻⁴%

The concentration of 4-chloro-3-hydroxybutylamide in the reactionmixture was 77.6 mM, as quantified in the same manner as used inExample 1. In contrast, β-hydroxy-γ-butyrolactone was below thedetection limit (1 mM).

EXAMPLE 9

Rhodococcus rhodochrous strain J-1 was cultured in the same manner asused in Example 7 to prepare a bacterial cell suspension.

(1 g, chemical purity: 92%) and the bacterial cell suspension (1 g) wereadded to 18.9 ml of 10 mM phosphate buffer (pH 6.6) and reacted at 5-10°C. for 10 hours. The yield of 4-chloro-3-hydroxybutylamide methacrylatewas 99%, as quantified using high performance liquid chromatographyunder the following conditions.

<Analysis Conditions for High Performance Liquid Chromatography>

Column: Inertsil ODS-3V (4.6 mm ID×25 mm), a product of GL Sciences,Inc.

Mobile phase: 0.1% phosphoric acid and 20% acetonitrile in water

Flow rate: 1 ml/min

Column temperature: 40° C.

Detection: differential refractometer (Japan Spectroscopic Co., Ltd.)

This solution was reacted in a water bath at 70° C. for 7 hours. Duringthe reaction, a pH controller was used to maintain a pH of 2.5 to 3.0 byadjusting with 24% by mass NaOH.

After completion of the reaction, the reaction mixture was extractedtwice with an equal volume of toluene and the combined toluene layerswere concentrated on a rotary evaporator to give an oily liquid (0.43g).

The purity of β-hydroxy-γ-butyrolactone methacrylate in the concentratedproduct was 62%, as quantified by high performance liquid chromatographyas described above.

EXAMPLE 10

Rhodococcus rhodochrous strain J-1 was cultured in the same manner asused in Example 7 to prepare a bacterial cell suspension.

2-Cyanobenzyl bromide (1 g) and the bacterial cell suspension (1 g) wereadded to 98 ml of 10 mM phosphate buffer (pH 7.0) and reacted at 10° C.for 3 days.

The yield of 4-chloro-3-hydroxybutylamide in the reaction mixture was99% or more, as quantified in the same manner as used in Example 9.

This solution was reacted in a water bath at 70° C. for 16 hours. Duringthe reaction, a pH controller was used to maintain a pH of 3.0 byadjusting with 24% by mass NaOH.

After the reaction mixture was extracted with toluene and evaporatedunder reduced pressure to remove the solvent, the residue was analyzedby IR, ¹H-NMR and ¹³C-NMR to confirm the production of γ-butyrolactonesrepresented by the following Formula (VII):

The yield was 21%, as quantified in the same manner as used in Example9.

EXAMPLE 11

An aqueous solution of 4-chloro-2-hydroxybutylamide (10% by mass, 100ml, containing 20 mM phosphate buffer) was reacted in a water bath at70° C. for 3 hours. During the reaction, a pH controller was used tomaintain a pH of 3.5 by adjusting with 24% by mass NaOH.

After the reaction mixture was extracted with ethyl acetate andevaporated under reduced pressure to remove the solvent, the residue wasanalyzed by IR, ¹H-NMR and ¹³C-NMR to confirm the production ofα-hydroxy-γ-butyrolactone. The amount of residual4-chloro-3-hydroxybutylamide was 1% or less of the initial amount andthe yield was 54%, as quantified in the same manner as used in Example1.

INDUSTRIAL APPLICABILITY

The present invention provides a method for producing γ-butyrolactonesor δ-valerolactones. According to the present invention, the method isindustrially useful because these lactones can be produced starting with4-halo-butylamides or the like, using fewer steps and with a reducedrisk of byproduct formation.

1. A method for producing a γ-butyrolactone, which comprises: reacting a 4-halo-butylamide of Formula (II):

wherein X represents a halogen atom, and R₁ to R₆ each independently represents a hydrogen atom or any desired substituent, with an aqueous medium at a pH of 2 to 4.5 to give a γ-butyrolactone of Formula (III):

wherein R₁ to R₆ each independently represents a hydrogen atom or any desired substituent, and wherein the 4-halo-butylamide of Formula (II) is a 4-halo-3-hydroxybutylamide; or wherein the 4-halo-butylamide of Formula (II) is produced by nitrile hydratase treatment of a 4-halo-butyronitrile having Formula (IV):

wherein X represents a halogen atom, and R₁ to R₆ each independently represents a hydrogen atom or any desired substituent.
 2. The method according to claim 1, wherein the 4-halo-butylamide of Formula (II) is a 4-halo-3-hydroxybutylamide.
 3. The method according to claim 1, wherein the 4-halo-butylamide of Formula (II) is produced by nitrile hydratase treatment of a 4-halo-butyronitrile having Formula (IV):

wherein X represents a halogen atom, and R₁ to R₆ each independently represents a hydrogen atom or any desired substituent.
 4. The method according to claim 3, wherein nitrile hydratase is produced by a transformant carrying a gene encoding nitrile hydratase.
 5. A method for producing a δ-valerolactone, which comprises: reacting a 5-halo-pentylamide of Formula (V):

wherein X represents a halogen atom, and R₁ to R₈ each independently represents a hydrogen atom or any desired substituent, with an aqueous medium to give a δ-valerolactone of Formula (VI):

wherein R₁ to R₈ each independently represents a hydrogen atom or any desired substituent.
 6. The method according to claim 2, wherein the reaction is carried out at a temperature of 30° C. to 100° C.
 7. The method according to claim 5, wherein the reaction is carried out at a temperature of 30° C. to 100° C.
 8. A method for producing a lactone, which comprises: reacting an aqueous medium with an amide compound of Formula (I) to produce a lactone; wherein Formula (I) is:

wherein X represents a halogen atom; n is an integer of 0, 1 or 2, and R, R′ and R₁ to R₆ each independently represents a hydrogen atom or any desired substituent; wherein n represents an integer of 1 or 2, or wherein X represents a halogen atom other than iodine, or wherein at least one of R, R′, R₁, R₂, R₃, R₄, R₅, or R₆ is not hydrogen.
 9. The method of claim 8, wherein n is 1 or
 2. 10. The method of claim 9, wherein X represents a halogen atom other than iodine.
 11. The method of claim 8, wherein at least one of R, R′, R₁, R₂, R₃, R₄, R₅, or R₆ is not hydrogen.
 12. The method of claim 8, which is conducted at an acidic pH.
 13. The method of claim 8, which is conducted at a pH ranging between 2 and 4.5.
 14. A method for producing a ε-caprolactone which comprises: reacting a 6-halo-hexylamide of Formula (I):

wherein n=2; X represents a halogen atom, and R, R′ and R₁ to R₆ each independently represents a hydrogen atom or any desired substituent; with an aqueous medium at a pH of 2 to 4.5 to give a ε-caprolactone.
 15. The method of claim 14, wherein the 6-halo-hexylamide is produced by nitrile hydratase treatment of the corresponding nitrile. 